Aromatic congeners of bilirubin: synthesis, stereochemistry, glucuronidation and hepatic transport

A new synthetic analog (1) of the bile pigment bilirubin-IX alpha (bilirubin, Fig. 1) with phenyl groups replacing vinyl was prepared by a constitutional scrambling reaction of a mixture of two new, symmetric phenylrubin analogs (2 and 3) of bilirubin-XIII alpha and III alpha. The former (2) with two endo-phenyls, and the latter (3) with two exo-phenyls were synthesized by condensation of a dipyrrylmethane dialdehyde with appropriate methylphenylpyrrolinones, which were prepared in several steps from 4-methyl-3-phenyl-2-(p-toluenesulfonyl)pyrrole, obtained by the Barton-Zard pyrrole synthesis. Nuclear Overhauser effect H-1 NMR studies of 1-3 confirm that, like their bilirubin equivalents, these yellow-orange pigments adopt an intramolecularly hydrogen-bonded ridge-tile conformation. Reverse phase HPLC and TLC suggest that 3 is less polar than 2, and that I has intermediate polarity. Large differences in the induced circular dichroism spectra of 1-3 were found in pH 7.4 aqueous buffered solutions of human serum albumin. Despite the presence of bulky, lipophilic phenyl groups, 1-3 are metabolized like natural bilirubin in rats and require glucuronidation by the same enzyme for canalicular secretion from the liver into bile. However, there are striking qualitative differences between the three pigments in the ratio of mono- to diglucuronides formed. Phenyl substituents at the exo positions of the lactam rings diminish the proportion of diglucuronide more than phenyl substituents at the endo positions. (C) 2001 Elsevier Science Ltd. All rights reserved.